Stroke is the second leading cause of death and a major cause of disability in the world. The current generation of thrombolytic agents, such as tissue-type plasminogen activator (tPA), only benefit a limited number of the potential patients with ischemic stroke, and the development of improved therapies for the treatment of stroke depends upon understanding the unique characteristics of the cerebrovasculature. The limited benefit of tPA may be due in part to unique activities that tPA has in the brain beyond its well established role as a fibrinolytic protease. In particular, animal studies have indicated that tPA interacts with at least two different cellular receptors expressed in the brain, and these associations have been linked to both neurotoxicity and altered blood-brain-barrier function. And while there are clear benefits to patents who receive early thrombolytic treatment, these recently described effects of tPA suggest that there are unique challenges for the use of thrombolytic therapy in ischemic stroke. Ideal treatments for ischemic stroke would simultaneously promote the reestablishment of vascular patency, inhibit the development of cerebral edema, reduce the incidence of hemorrhagic transformation, and provide direct neuroprotection. Our previous studies have shown that the natural inhibitor of tPA in the CNS, neuroserpin, appears to act as a neuroprotective agent that can promote significant neuronal survival and cell recovery after stroke. In addition our studies suggest that antagonism within the CNS of the tPA receptor, the LDL Receptor Related Protein (LRP), dramatically reduces blood-brain-barrier dysfunction following stroke. Thus, this proposal will test the hypothesis that during cerebral ischemia tPA, neuroserpin, and LRP function together within the brain to regulate blood-brain-barrier permeability and neuronal survival. We will investigate the mechanisms of this regulation, and test the hypothesis that targeting these interactions will lead to the development of more effective therapies for the treatment of ischemic stroke. We will also evaluate novel treatments for stroke by combining various thrombolytic and neuroprotective agents, and comparing the efficacy of these combined therapies in murine models of stroke.